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Tài liệu Báo cáo khoa học: Switching of the homooligomeric ATP-binding cassette transport complex
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Tài liệu Báo cáo khoa học: Switching of the homooligomeric ATP-binding cassette transport complex

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Mô tả chi tiết

Switching of the homooligomeric ATP-binding cassette

transport complex MDL1 from post-translational

mitochondrial import to endoplasmic reticulum insertion

Simone Gompf1

, Ariane Zutz1

, Matthias Hofacker1

, Winfried Haase2

, Chris van der Does1

and Robert Tampe´

1

1 Institute of Biochemistry, Biocenter, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

2 Max-Planck Institute of Biophysics, Structural Biology, Frankfurt am Main, Germany

ATP-binding cassette (ABC) transporters belong to a

large family of membrane proteins found in all three

kingdoms of life. The chemical energy of ATP is used

to drive uphill transport of a broad range of solutes

across membranes [1–3]. ABC transporters have a

conserved domain organization consisting of two trans￾membrane domains (TMDs) and two nucleotide-bind￾ing domains (NBDs). The TMDs form a translocation

pore, whereas the NBDs catalyze ATP hydrolysis.

The ABC half-transporter multidrug resistance like

protein 1 (MDL1), composed of a TMD followed by a

NBD, is located in the inner mitochondrial membrane

(IMM) of Saccharomyces cerevisiae. It has been sug￾gested to be involved in the export of 6-mer to 20-mer

peptides, derived from proteolysis of nonassembled

inner membrane proteins by the m-AAA (i.e. matrix￾oriented ATPase associated with a variety of cellular

activities) protease [4]. It has been further reported

that MDL1 mediates resistance against oxidative stress

and can partially complement the function of ABC

transporter of mitochondria (ATM) 1 [5]. Deletion of

ATM1 in S. cerevisiae results in a severe growth defect

because ATM1 is essential for the biogenesis of cyto￾solic iron-sulfur (Fe-S) proteins [6].

Keywords

ABC transporter; ER targeting; membrane

protein trafficking transport ATPase;

mitochondrial import; mitochondrial

targeting sequence

Correspondence

R. Tampe´, Institute of Biochemistry,

Biocenter, Johann Wolfgang Goethe￾University, Max-von-Laue-Strasse 9,

D-60348 Frankfurt am Main, Germany

Fax: +49 (0) 69 798 29495

Tel: +49 (0) 69 798 29475

E-mail: tampe@em.uni-frankfurt.de

Website: http://www.biochem.

uni-frankfurt.de

(Received 25 May 2007, revised 5 July

2007, accepted 20 August 2007)

doi:10.1111/j.1742-4658.2007.06052.x

The ATP-binding cassette transporter MDL1 of Saccharomyces cerevisiae

has been implicated in mitochondrial quality control, exporting degradation

products of misassembled respiratory chain complexes. In the present study,

we identified an unusually long leader sequence of 59 amino acids, which

targets MDL1 to the inner mitochondrial membrane with its nucleotide￾binding domain oriented to the matrix. By contrast, MDL1 lacking this lea￾der sequence is directed into the endoplasmic reticulum membrane with the

nucleotide-binding domain facing the cytosol. Remarkably, in both target￾ing routes, the ATP-binding cassette transporter maintains its intrinsic

properties of membrane insertion and assembly, leading to homooligomeric

complexes with similar activities in ATP hydrolysis. The physiological con￾sequences of both targeting routes were elucidated in cells lacking the mito￾chondrial ATP-binding cassette transporter ATM1, which is essential for

biogenesis of cytosolic iron-sulfur proteins. The mitochondrial MDL1 com￾plex can complement ATM1 function, whereas the endoplasmic reticulum￾targeted version, as well as MDL1 mutants deficient in ATP binding and

hydrolysis, cannot overcome the Datm1 growth phenotype.

Abbreviations

ABC, ATP-binding cassette; ATM, ABC transporter of mitochondria; ER, endoplasmic reticulum; 5-FOA, 5-fluoroorotic acid; IMM, inner

mitochondrial membrane; MDL1, multidrug resistance like protein 1; MTS, mitochondrial targeting signal; NBD, nucleotide-binding domain;

SC, synthetic complete; TIM, translocase of the inner mitochondrial membrane; TOM, translocase of the outer mitochondrial membrane;

TMD, transmembrane domain.

5298 FEBS Journal 274 (2007) 5298–5310 ª 2007 The Authors Journal compilation ª 2007 FEBS

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